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Structure and autoregulation of the yeast Hst2 homolog of Sir2

Nature Structural & Molecular Biology volume 10, pages 864–871 (2003)Cite this article

Abstract

Yeast Hst2 (yHst2) is a member of the silencing information regulator 2 (Sir2) family of NAD+-dependent protein deacetylases that are implicated in transcriptional silencing, DNA repair, genome stability and longevity. The X-ray crystal structure of the full-length yHst2 protein reveals a central catalytic core domain fold that is characteristic of the other Sir2 homologs, and C- and N-terminal extensions that interact with the NAD+ and acetyl-lysine substrate-binding sites, respectively, suggesting an autoregulatory function for these domains. Moreover, the N-terminal extension mediates formation of a homotrimer within the crystal lattice. Enzymatic and sedimentation equilibrium studies using deletion constructs of yHst2 support the involvement of the N- and C-terminal yHst2 regions and trimer formation in catalysis by yHst2. Together, these studies indicate that the sequence-divergent N- and C-terminal regions of the eukaryotic Sir2 proteins may have a particularly important role in their distinct substrate-binding properties, biological activities or both.

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Figure 1: Structure of yeast Hst2 and other Sir2 proteins.
Figure 2: Sequence alignment of Sir2 proteins.
Figure 3: NAD+-binding site of yeast Hst2.
Figure 4: The acetyl-lysine substrate-binding site and trimer formation by yeast Hst2.
Figure 5: Solution oligomerization and kinetic properties of yeast Hst2 proteins.

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Acknowledgements

We thank L. Guarente, L. Pillus, D. Speicher and S. Harper for useful discussions, and A. Joachimiak, R. Zhang, N. Duke and the SBC-CAT staff for access to and assistance with the 19BM beamline at APS. This work was supported by the US National Institutes of Health grants to R.M. and by a grant from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health, awarded to the Wistar Institute.

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  1. The Wistar Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Kehao Zhao, Xiaomei Chai, Adrienne Clements & Ronen Marmorstein

  2. Department of Chemistry, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Ronen Marmorstein

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Correspondence to Ronen Marmorstein.

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Zhao, K., Chai, X., Clements, A. et al. Structure and autoregulation of the yeast Hst2 homolog of Sir2. Nat Struct Mol Biol 10, 864–871 (2003). https://doi.org/10.1038/nsb978

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